Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

Kim, Dae-Hyun; Lee, Jaetae; Lee, Inkyu; Ha, Jeoung‐Hee

doi:10.1248/bpb.31.255

Cited by 15 publications

(18 citation statements)

References 35 publications

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“…Apigenin, on the other hand, has low cytotoxicity, as also suggested by our findings. 27,[33][34][35][36][37] BrdU ELISA assay confirmed the most effective apigenin dose (90 lM) and incubation period (72 hours).…”

Section: Discussionmentioning

confidence: 76%

Evaluation of the Effects of the Flavonoid Apigenin on Apoptotic Pathway Gene Expression on the Colon Cancer Cell Line (HT29)

Turktekin

Konac

Onen

et al. 2011

Journal of Medicinal Food

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Apigenin (4',5,7-trihydroxyflavone) is one of the leading components supporting targeted treatment options. We explored the cytotoxic and apoptotic effects of various doses of apigenin administered alone and together with 5-fluorouracil (5-FU)-a chemotherapeutic agent with high cytotoxicity-for different incubation periods, on morphologic, DNA, RNA (messenger RNA [mRNA]), and protein levels on the p53 mutant HT29 human colon adenocarcinoma cell line. Treatment with apigenin alone for a 72-hour incubation at 90-μM dose resulted in an apoptotic percentage of 24.92% (P=.001). A higher percentage (29.13%) was observed after treatment with the same dose of apigenin plus 5-FU for the same incubation period (P=.001). These results were confirmed as mRNA and protein expression levels of caspase-3 increased 2.567-fold and mRNA expression levels of caspase-8 increased 3.689-fold compared with the control group. On the other hand, mRNA expression levels of mammalian target of rapamycin (mTOR) and cyclin D1 (CCND1) decreased by 0.423-fold and 0.231-fold, respectively. To our knowledge this is the first study showing that treatment with apigenin alone results in cell cycle arrest through activation of caspase cascade and stimulation of apoptosis in HT29 cells. It also shows that use of apigenin plus 5-FU further increases this effect. This study draws attention to the probable clinical effectiveness of apigenin plus a chemotherapeutic agent with high cytotoxicity. It also highlights the induction of desirable apoptotic effects by targeting the caspase cascade pathway through administration of reduced doses for shorter incubation periods.

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Section: Discussionmentioning

confidence: 76%

Evaluation of the Effects of the Flavonoid Apigenin on Apoptotic Pathway Gene Expression on the Colon Cancer Cell Line (HT29)

Turktekin

Konac

Onen

et al. 2011

Journal of Medicinal Food

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“…Consistent with this finding, in the present study, upregulation of PBR mRNA expression by colorectal (SNU-C4) adenocarcinoma cells was observed after treatment for 6 days with flavonoids and diazepam. In a previous study by the current authors [5], inhibition of survival of SNU-C4 cells by treatment for 6 days with flavonoids and diazepam was about twofold higher than that of cells treated for 3 days. These results suggest that enhanced activation of PBR due to upregulation of PBR mRNA expression partially contributed to the anticancer cytotoxicity of cells treated for 6 days.…”

Section: Discussionmentioning

confidence: 44%

“…In presence of 10 -6 M apigenin and diazepam, the IC 50 value of 5-FU-treated cells was significantly (P \ 0.05) decreased to 0.08 ± 0.03 and 0.07 ± 0.02 lM, respectively, from 3.9 ± 0.6 lM in the absence of apigenin or diazepam. In a previous study by the current authors [5], apigenin, an anxiolytic flavonoid with partial agonistic activity towards central-type BZD receptors, and diazepam, a prototype sedative, showed concentration-dependent inhibition of SNU-C4 cell survival, with IC 50 values for apigenin and diazepam of 2.3 ± 0.2 and 5.5 ± 1.2 lM, respectively. Thus, 10 -6 M apigenin, fisetin, and diazepam were used in this study.…”

Section: Resultsmentioning

confidence: 62%

“…The proapoptotic 1,4-benzodiazepine (BZD) has also been shown to affect growth and survival of malignant B cells [4]. In a previous study by the current authors [5], diazepam exhibited plant flavonoid-like antiproliferative cytotoxicity in SNU-C4 human colorectal and MDA-MB-231 human breast cancer cells. However, routine use of 5 mg diazepam per os before the intravenous administration of fluorodeoxyglucose (FDG) has been reported to render positron emission tomography (PET) imaging ineffective [6].…”

Section: Introductionmentioning

confidence: 99%

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In vitro antiproliferative characteristics of flavonoids and diazepam on SNU-C4 colorectal adenocarcinoma cells

Lee

et al. 2008

J Nat Med

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The need for beneficial use of sedatives in oncologic patients is increasing. Therefore, in this study, antiproliferative characteristics of herbal and synthetic sedatives were examined in vitro in SNU-C4 human colorectal adenocarcinoma cells. Apigenin (50% inhibition concentration, IC(50) = 1.8 +/- 0.5 microM) and diazepam (IC(50) = 7.0 +/- 0.5 microM) showed concentration-dependent inhibition of SNU-C4 cancer cell survival. Efficacy of cancer cell survival inhibition by apigenin and diazepam was much lower than that of 5-fluorouracil (5-FU), a known chemotherapeutic drug. However, 10(-6) M concentration of apigenin and diazepam potentiated 5-FU-induced cytotoxicity. In SNU-C4 cells, 10(-6) M concentrations of diazepam, flumazenil (Ro15-1788), Ro5-4864, or PK11195, all ligands for central- or peripheral-type benzodiazepine (BZD) receptors, inhibited cell survival like the flavonoid apigenin (4',5,7-trihydroxyflavone) and fisetin (3,7,3',4'-tetrahydroxyflavone). Also like the plant flavonoids, treatment with 10(-6) M concentration of diazepam for 3 days hardly affect the peripheral-type BZD receptor (PBR) messenger RNA (mRNA) expression and inhibited glucose utilization of SNU-C4 cells. Treatment with flavonoids or diazepam for 6 days upregulated PBR mRNA expression and cell cytotoxicity of SNU-C4 cells. Furthermore, treatment with 10(-6) M concentration of apigenin, a natural sedative material originating from traditional herbs, positively modulated BZD-induced antiproliferative cytotoxicity in SNU-C4 cells. Overall, the in vitro antiproliferative activity on SNU-C4 cancer cells of herbal sedatives, such as apigenin, plus additive enhancement of synthetic BZD- and 5-FU-induced antiproliferative activities, were shown. In conclusion, this study provides experimental basis for advanced trial in the future.

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“…Several animal studies reported that benzodiazepines increased the risk of thyroid cancer or liver cancer . Conversely, in vitro laboratory studies indicated that benzodiazepines might inhibit the proliferation of pituitary tumor cells or have antitumor effects on colorectal and breast adenocarcinoma cells …”

Section: Introductionmentioning

confidence: 99%

Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies

et al. 2016

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Several observational epidemiological studies have reported inconsistent results on the association between the use of benzodiazepine and the risk of cancer. We investigated the association by using a meta‐analysis. We searched PubMed, EMBASE, and the bibliographies of relevant articles to locate additional publications in January 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. Of 796 articles meeting our initial criteria, a total of 22 observational epidemiological studies with 18 case‐control studies and 4 cohort studies were included in the final analysis. Benzodiazepine use was significantly associated with an increased risk of cancer (odds ratio [OR] or relative risk [RR] 1.19; 95% confidence interval 1.16–1.21) in a random‐effects meta‐analysis of all studies. Subgroup meta‐analyses by various factors such as study design, type of case‐control study, study region, and methodological quality of study showed consistent findings. Also, a significant dose‐response relationship was observed between the use of benzodiazepine and the risk of cancer (p for trend <0.01). The current meta‐analysis of observational epidemiological studies suggests that benzodiazepine use is associated with an increased risk of cancer.

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Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

Cited by 15 publications

References 35 publications

Evaluation of the Effects of the Flavonoid Apigenin on Apoptotic Pathway Gene Expression on the Colon Cancer Cell Line (HT29)

Evaluation of the Effects of the Flavonoid Apigenin on Apoptotic Pathway Gene Expression on the Colon Cancer Cell Line (HT29)

In vitro antiproliferative characteristics of flavonoids and diazepam on SNU-C4 colorectal adenocarcinoma cells

Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies

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